The present invention relates to macrocyclic aminophosphonic acid complexes for the treatment of cancer, especially the treatment of calcific tumors, to the method of treatment of calcific tumors, and to compositions having as their active ingredient a radionuclide complexed with a macrocyclic aminophosphonic acid.
The development of bone metastases is a common and often catastrophic event for a cancer patient. The pain, pathological fractures, frequent neurological deficits and forced immobility caused by these metastatic lesions significantly decrease the quality of life for the cancer patient. The number of patients that contract metastatic disease is large since nearly 50% of all patients who contract breast, lung or prostate carcinoma will eventually develop bone metastases. Bone metastases are also seen in patients with carcinoma of the kidney, thyroid, bladder, cervix and other tumors, but collectively, these represent less than 20% of patients who develop bone metastases. Metastatic bone cancer is rarely life threatening and occasionally patients live for years following the discovery of the bone lesions. Initially, treatment goals center on relieving pain, thus reducing requirements for narcotic medication and increasing ambulation. Clearly, it is hoped that some of the cancers can be cured.
The use of radionuclides for treatment of cancer metastatic to the bone dates back to the early 1950's. It has been proposed to inject a radioactive particle-emitting nuclide in a suitable form for the treatment of calcific lesions. It is desirable that such nuclides be concentrated in the area of the bone lesion with minimal amounts reaching the soft tissue and normal bone. Radioactive phosphorus (P-32 and P-33) compounds have been proposed, but the nuclear and biolocalization properties limit the use of these compounds. (Kaplan, E., et al., Journal of Nuclear Medicine, 1(1), p. 1, 1960); (U.S. Pat. No. 3,965,254).
Another attempt to treat bone cancer has been made using phosphorus compounds containing a boron residue. The compounds were injected into the body (intravenously) and accumulated in the skeletal system. The treatment area was then irradiated with neutrons in order to activate the boron and give a therapeutic radiation dose. (U.S. Pat. No. 4,399,817).
The use of radionuclides for calific tumor therapy is discussed in published European patent application 176,288 where the use of Sm-153, Gd-159, Ho-166, Lu-177 or Yb-175 complexed with certain ligands selected from ethylenediaminetetraacetic acid (EDTA) or hydroxyethylenediaminetriacetic acid (HEEDTA) is disclosed.
In the above mentioned procedures, it is not possible to give therapeutic doses to the tumor without substantial damage to normal tissues. In many cases, especially for metastatic bone lesions, the tumor has spread throughout the skeletal system and amputation or external beam irradiation is not practical. (Seminars in Nuclear Medicine, Vol. IX, No. 2, April, 1979).
The use of Re-186 complexed with a diphosphonate has also been proposed. [Mathieu, L. et al., Int. J. Applied Rad. & Isotopes, 30, 725-727 (1979); Weinenger, J., Ketring, A. R., et al., Journal of Nuclear medicine, 24(5), P125 (1983)]. However, the preparation and purification needed for this complex limits its utility and wide application.
Strontium-89 has also been proposed for patients with metastatic bone lesions. However, the long half-life (50.4 days), high blood levels and low lesion to normal bone ratios limit the utility. [Firusian, N., Mellin, P., Schmidt, C. G., The Journal of Urology, 116, 764 (1976): Schmidt, C. G., Firusian, N., Int. J. Clin. Pharmacol., 93, 199-205, (1974)].
A palliative treatment of bone metastases has been reported which employed I-131 labelled .alpha.-amino(3-iodo-4-hydroxybenzylidene)diphosphonate [Eisenhut, M., Journal of Nuclear Medicine, 25(12), 1356-1361 (1984)]. The use of radioiodine as a therapeutic radionuclide is less than desirable due to the well known tendency of iodine to localize in the thyroid. Eisenhut lists iodide as one of the possible metabolites of this compound.
The present invention is directed to at least one composition comprised of a radionuclide complexed with a macrocyclic aminophosphonic acid containing 1,4,7,10-tetraazacyclododecane, or its physiologically acceptable salt, which causes minimal damage to normal tissue when administered in the method of the invention. Surprisingly, the present complex is more effective at a lower ligand to metal molar ratio than has been known previously in the art.